The transferrin receptor (TfR) (also known as CD71), a type II transmembrane glycoprotein made of two 90-kDa monomers on the surface of cells, is a vital protein which is involved in iron homeostasis and the regulation of cell growth (reviewed in Daniels T R et al., Clin Immunol. 121(2):144-58, 2006). The expression amount of transferrin receptor is significantly upregulated in highly proliferating cells, and the increased expressions for the transferrin receptors at each cancer stage have differences, and differences in the expression amounts can help to avoid incorrect determinations of the cancer stage (Shindelman J E et al., Int J Cancer. 27:329-34, 1981; Sciot Ret al., Histopathology. 16:59-62, 1990; Le N T et al., Biochim Biophys Acta 1603:31-46, 2002). Since transferrin receptors are strongly expressed by most malignant cells, are present on cell surfaces, and have the properties of being bound and detected easily and mediated by endocytosis, they have long been considered an effective target for targeted cancer therapies.
A number of anti-transferrin receptor monoclonal antibodies have been demonstrated to inhibit the growth of many cell types. For example, the murine monoclonal anti-human transferrin receptor antibody 42/6, the first to use an anti-transferrin receptor antibody in a clinical trial, is confirmed to be able to inhibit malignant cell growth (Brooks D et al., Clin Cancer Res. 1(11):1259-65, 1995). In addition, by transferrin receptor-mediated endocytosis, therapeutic agents can be delivered to tumor cells through transferrin receptors. Moreover, the high expression level of transferrin receptor is also found on the blood brain barrier, which makes of interest for therapeutic or diagnostic approaches in brain diseases. For instance, the anti-transferrin receptor antibody OX-26 could be used as a carrier for the delivery of drugs across the blood-brain barrier (Friden P M et al. Proc Natl Acad Sci U S A. 88(11):4771-5, 1991).
The use of monoclonal antibodies in the clinical treatment of cancer started in the early 1980s. Unfortunately, murine monoclonal antibodies have been far from ideal in the treatment of humans. Due to the short half-life of the murine monoclonal antibodies in human bodies, the murine monoclonal antibodies require frequent administration to maintain therapeutic levels (Manuel L. Penichetn and Sherie L. Morrison, Drug Dev. Res. 61:121-136, 2004). In addition, patients treated with these murine antibodies often produce human anti-mouse antibodies (HAMA) that neutralizes the murine monoclonal antibodies, decreases the half-life of the murine monoclonal antibodies, and in some cases was associated with severe allergic reactions (Abramowicz D et al., N Engl. J. Med. 327:736, 1992).